Prostate cancer is the second leading cause of cancer death in men in the United States. Localized prostate cancer can be cured by androgen ablation, but when the disease escapes the confines of the gland, the prospects for cure decrease drastically and the disease becomes castrate resistant. Bone is the primary site of castrate-resistant disease progression, which is associated with a poor prognosis. The fibroblast growth factor (FGF)/FGF receptor (FGFR) complex, a signaling axis involving multiple FGF ligands and receptors, mediates tumor-stromal interactions and is one ofthe most commonly altered signaling pathways during prostate cancer progression. Expression of FGFR1, multiple FGF ligands, and FGFR adaptor, FRS2a has been observed in prostate cancer epithelial cells. Our recent studies have defined a mouse model of prostate cancer highly dependent on FGF signaling, and have implicated FGFQ in the osteoblastic progression of human prostate cancer cells in bone. The results of our preliminary studies support a notion that during bone metastasis, the prostate cancer cells that aberrantly express both FGF and FGFRs creates a new compartment in bone as source and recipient of additional FGF-mediated signaling, thus subverting homeostasis. The implication ofthe FGF axis in prostate cancer progression suggests that FGFR blockade represents a new therapeutic opportunity for men with castrate-resistant prostate cancer. Recently, TKI258, a receptor tyrosine kinase inhibitor (TKl) with strong activity against FGFR1-3 (IC50 < 40 nM), has become available and is being used as an experimental new drug for solid tumors. The main goal of this proposed project is to establish the feasibility of using TKI258 to modulate FGF signaling in men with castrate-resistant prostate cancer and to correlate FGF signaling modulation with clinical disease progression. We will assess the effect of TKI258 on human prostate cancer xenografts growing in the prostate and bone of castrated immunodeficient male mice (Aim 1), and also on mouse models of prostate cancer (Aim 2) to identify markers of response to TK1258 therapy directly related to FGF signaling. We will then perform a proof-of-principle clinical study with TKI258 in men with castrate-resistant prostate cancer and bone marrow infiltration (Aim 3). The study will create an annotated tissue resource and will permit validation of FGF signaling responsive markers emerging from Aims 1 and 2. This will be the first clinical study to assess the effect of TKI258 in prostate cancer. RELEVANCE (See instructions): Prostate cancer is the second leading cause of cancer death in men in the United States. In the proposed study we will perform a proof-of-principle clinical study with a receptor tyrosine kinase inhibitor, TK1258 in men with castrate-resistant prostate cancer and bone marrow infiltration. The results of this study will be the foundation for development of further therapies of prostate cancer patients based on targeting the fibroblast growth factor signaling pathway.